Modulators for amyloid beta

ABSTRACT

The invention relates to compounds of formula 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R3, R 4 , and Ar are as defined in the specification and claims, or to pharmaceutically active acid addition salts of such compounds. Compounds of formula I are modulators for amyloid beta and may be useful for the treatment or prevention of a disease associated with the deposition of β-amyloid in the brain, in particular Alzheimer&#39;s disease, and other diseases such as cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica and Down syndrome.

PRIORITY TO RELATED APPLICATION(S)

This application is a continuation of U.S. application Ser. No.13/437,057, filed Apr. 2, 2012, now pending which is a continuation ofU.S. application Ser. No. 12/572,327, filed Oct. 2, 2009, now abandoned;which claims the benefit of European Patent Application No. 08166228.0,filed Oct. 9, 2008. The entire contents of the above-identifiedapplications are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

Alzheimer's disease (AD) is the most common cause of dementia in laterlife. Pathologically, AD is characterized by the deposition of amyloidin extracellular plaques and intracellular neurofibrillary tangles inthe brain. The amyloid plaques are mainly composed of amyloid peptides(A13 peptides) which originate from the β-Amyloid Precursor Protein(APP) by a series of proteolytic cleavage steps. Several forms of APPhave been identified of which the most abundant are proteins of 695, 751and 770 amino acids length. They all arise from a single gene throughdifferential splicing. The Aβ peptides are derived from the same domainof the APP.

Aβ peptides are produced from APP through the sequential action of twoproteolytic enzymes termed β- and γ-secretase. β-Secretase cleaves firstin the extracellular domain of APP just outside of the trans-membranedomain (TM) to produce a C-terminal fragment of APP containing the TM-and cytoplasmatic domain (CTFβ). CTFβ is the substrate for γ-secretasewhich cleaves at several adjacent positions within the TM to produce theAβ peptides and the cytoplasmic fragment. Various proteolytic cleavagesmediated by γ-secretase result in Aβ peptides of different chain length,e.g. Aβ38, Aβ40 and Aβ42. The latter one is regarded to be the morepathogenic amyloid peptide because of its strong tendency to formneurotoxic aggregates.

The β-secretase is a typical aspartyl protease. The γ-secretase is aproteolytic activity consisting of several proteins, its exactcomposition is incompletely understood. However, the presenilins areessential components of this activity and may represent a new group ofatypical aspartyl proteases which cleave within the TM of theirsubstrates and which are themselves polytopic membrane proteins. Otheressential components of γ-secretase may be nicastrin and the products ofthe aphl and pen-2 genes. Proven substrates for γ-secretase are the APPand the proteins of the Notch receptor family, however, γ-secretase hasloose substrate specificity and may cleave further membrane proteinsunrelated to APP and Notch.

The γ-secretase activity is absolutely required for the production of Aβpeptides. This has been shown both by genetic means, i.e., ablation ofthe presenilin genes and by low-molecular-weight inhibitory compounds.Since according to the amyloid hypothesis for AD the production anddeposition of Aβ is the ultimate cause for the disease, it is thoughtthat selective and potent inhibitors of γ-secretase will be useful forthe prevention and treatment of AD.

An alternative mode of treatment is the modulation of the γ-secretaseactivity which results in a selective reduction of the Aβ42 production.This will result in to an increase of shorter Aβ isoforms, such as Aβ38,Aβ37 or others, which have reduced capability for aggregation and plaqueformation, and hence less neurotoxic. Compounds which show this effecton modulating γ-secretase activity include certain non-steroidalanti-inflammatory drugs (NSAIDs) and related analogues (Weggen et al.Nature, 414 (2001) 212-16).

Numerous documents describe the current knowledge on γ-secretasemodulation, for example the following publications:

-   Morihara et al, J. Neurochem., 83 (2002) 1009-12-   Jantzen et al, J. Neuroscience, 22 (2002) 226-54-   Takahashi et al, J. Biol. Chem., 278 (2003) 18644-70-   Beher et al, J. Biol. Chem. 279 (2004) 43419-26-   Lleo et al, Nature Med. 10 (2004) 1065-6-   Kukar et al, Nature Med. 11 (2005) 545-50-   Perretto et al, J. Med. Chem. 48 (2005) 5705-20-   Clarke et al, J. Biol. Chem. 281 (2006) 31279-89-   Stock et al, Bioorg. Med. Chem. Lett. 16 (2006) 2219-2223-   Narlawar et al, J. Med. Chem. 49 (2006) 7588-91

SUMMARY OF THE INVENTION

The invention provides compounds of formula I

wherein

-   R¹ is hydrogen, lower alkyl or is lower alkyl substituted by    hydroxy;-   R² is hydrogen, lower alkoxy or lower alkyl;-   R³ and R⁴ are each independently hydrogen, halogen, lower alkyl,    C(O)O-lower alkyl, OR′, NR″R′″, lower alkyl substituted by halogen    or hydroxy, or is phenyl or benzyl, each of which is optionally    substituted by one or two halogen atoms;-   R′ is lower alkyl, or is phenyl, benzyl or pyridinyl, wherein    phenyl, benzyl or pyridinyl are each optionally substituted by one    or more halogen, lower alkyl or lower alkyl substituted by fluoro;-   R″ is hydrogen or lower alkyl;-   R′″ is lower alkyl, lower alkyl substituted by one or two hydroxy    groups, CH(CH₂OH)-phenyl, —(CH₂)₂O-lower alkyl, or phenyl    substituted by halogen, or-   R″ and R′″ together with the N-atom to which they are attached form    a heterocyclic ring, optionally substituted by one or more lower    alkyl, CH₂C(O)O-lower alkyl, or CH₂C(O)OH;-   Ar is a five-membered heteroaryl group;    and pharmaceutically active acid addition salts thereof.

The invention provides all forms of optically pure enantiomers,racemates, or diastereomeric mixtures of the compounds of the invention.

The invention also provides pharmaceutical compositions containingcompounds of formula I or pharmaceutically acceptable salts thereof anda pharmaceutically acceptable carrier. The invention further providesmethods for the manufacture of the compounds and compositions of theinvention.

Compounds of formula I are modulators for amyloid beta and thus, theyare useful for the treatment or prevention of a disease associated withthe deposition of β-amyloid in the brain, in particular Alzheimer'sdisease, and other diseases such as cerebral amyloid angiopathy,hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D),multi-infarct dementia, dementia pugilistica and Down syndrome.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions of general terms used herein applyirrespective of whether the terms in question appear alone or incombination. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralforms unless the context clearly dictates otherwise.

As used herein, the term “lower alkyl” denotes a saturated straight- orbranched-chain hydrocarbon group containing from 1 to 7 carbon atoms,for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl,2-butyl, t-butyl and the like. Preferred alkyl groups are groups with1-4 carbon atoms.

As used herein, the term “halogen” denotes a chlorine, fluorine,bromine, or iodine, with fluorine being preferred.

The term “lower alkyl substituted by halogen” denotes a lower alkylgroup as defined hereinabove which is substituted by one or more,preferably one, two or three halogen atom(s), i.e. chlorine, iodine,fluorine or bromine.

As used herein, the term “lower alkyl substituted by fluoro” denotes analkyl group as defined above, wherein at least one hydrogen atom isreplaced by fluoro, for example CF₃, CHF₂, CH₂F, CH₂CF₃, CH₂CH₂CF₃,CH₂CF₂CF₃, CH₂CF₂CF₂CF₃, CH₂CH₂CF₂CF₃ and the like.

The term “lower alkyl substituted by hydroxy” denotes a lower alkylgroup as defined hereinabove which is substituted by one or more,hydroxy group(s),

As used herein, the term “lower alkoxy” denotes a lower alkyl group asdefined above that is attached via an oxygen atom.

As used herein, the term “five-membered heteroaryl group” denotes anaromatic ring having five ring atoms, wherein at least two ring atomsare heteroatoms, selected from the group consisting of N, O and S, forexample oxazolyl, [1,2,4]triazolyl, imidazol-1-yl, thiazolyl,isothiazolyl, isoxazolyl, pyrazol-1-yl, [1,2,4]-oxadiazol-5-yl or[1,3,4]-oxadiazol-2-yl. Preferred is the imidazolyl group.

The term “heterocyclic ring” denotes a five or six membered non aromaticring containg a N atom in the 1-position, wherein the remaining ringatoms are selected from N, O and S, for example the groupspiperidine-1-yl, morpholinyl, thiomorpholin or piperazine.

“Pharmaceutically acceptable,” such as pharmaceutically acceptablecarrier, excipient, etc., means pharmacologically acceptable andsubstantially non-toxic to the subject to which the particular compoundis administered.

The term “pharmaceutically acceptable acid addition salts” embracessalts with inorganic and organic acids, such as hydrochloric acid,nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid,fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid,methane-sulfonic acid, p-toluenesulfonic acid and the like.

“Therapeutically effective amount” means an amount that is effective toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

Preferred compounds are those where Ar is oxazolyl, [1,2,4]triazolyl,imidazol-1-yl, thiazolyl, isothiazolyl, isoxazolyl, pyrazol-1-yl,[1,2,4]-oxadiazol-5-yl or [1,3,4]-oxadiazol-2-yl.

Preferred compounds are those wherein Ar is imidazol-1-yl.

Preferred compounds from this group are those, wherein one of R³ or R⁴is NR″R′″ and R″ and R′″ together with the N-atom to which they areattached form a heterocyclic ring, optionally substituted by one or morelower alkyl, CH₂C(O)O-lower alkyl or CH₂C(O)OH, for example thefollowing compounds:

-   [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4-methoxy-6-piperidin-1-yl-[1,3,5]triazin-2-yl)-amine;-   (1-{4-methoxy-6-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-[1,3,5]triazin-2-yl}-piperidin-4-yl)-acetic    acid ethyl ester; and-   (1-{4-methoxy-6-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-[1,3,5]triazin-2-yl}-piperidin-4-yl)-acetic    acid.

Further preferred compounds are those, wherein Ar is imidazol-1-yl andone of R³ or R⁴ is OR′, for example the following compounds

-   [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-methoxy-6-(2-trifluoromethyl-phenoxy)-[1,3,5]triazin-2-yl]-amine;-   [4-(4-fluoro-phenoxy)-6-methoxy-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine;-   [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-methoxy-6-(3,4,5-trifluoro-phenoxy)-[1,3,5]triazin-2-yl]-amine;-   [4-(2,4-dichloro-phenoxy)-6-methoxy-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine;-   [4-(2-chloro-pyridin-3-yloxy)-6-methoxy-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine;-   [4-isopropoxy-6-(2-trifluoromethyl-phenoxy)-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine;-   (4,6-diisopropoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine;-   [4,6-bis-(2-trifluoromethyl-phenoxy)-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine;    and-   [4-(4-chloro-benzyloxy)-6-methoxy-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine.

Further preferred compounds are those, wherein Ar is imidazol-1-yl andone of R³ or R⁴ is NR″R′″ and R″ is H or lower alkyl and R′″ is loweralkyl, lower alkyl substituted by one or two hydroxy groups,—(CH₂)₂OCH₃, or phenyl substituted by halogen, for example the followingcompounds

-   N-(4-chloro-phenyl)-6-methoxy-N′-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[1,3,5]triazine-2,4-diamine;-   N-(4-chloro-phenyl)-6-methoxy-N′-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N-methyl-[1,3,5]triazine-2,4-diamine;-   N-(4-chloro-phenyl)-N′-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N-methyl-[1,3,5]triazine-2,4-diamine;    and-   N-(4-chloro-phenyl)-6-isopropoxy-N′-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N-methyl-[1,3,5]triazine-2,4-diamine.

Preferred compounds are those where one of R³ and R⁴ is halogen.

Also preferred are compounds where one of R³ and R⁴ is lower alkyl.

Further preferred are compounds where one of R³ and R⁴ is C(O)O-loweralkyl.

Preferred compounds are those where one of R³ and R⁴ is OR′.

Other preferred compounds are those where one of R³ and R⁴ is NR″R′″.

Still other preferred compounds are those where one of R³ and R⁴ islower alkyl substituted by halogen or hydroxyl.

Further, preferred compounds are those where one of R³ and R⁴ is phenyloptionally substituted by one or two halogen atoms.

Preferred compounds are those where one of R³ and R⁴ is benzyloptionally substituted by one or two halogen atoms.

The present compounds of formula I and their pharmaceutically acceptablesalts can be prepared by methods known in the art, for example, byprocesses described below, which process comprises

a) reacting a compound of formula

with a compound of formula

to obtain a compound of formula

wherein the substituents are as defined above, or

b) reacting a compound of formula

with a compound of formula

R³H

to obtain a compound of formula

wherein the substituents are as defined above, or

c) reacting a compound of formula

with a compound of formula

R⁴H

to obtain a compound of formula

and, if desired, converting the compounds obtained into pharmaceuticallyacceptable acid addition salts.

The compounds of formula I can be prepared in accordance with processvariant a), b) or c) and with the following schemes 1, 2 and 3.

The present compounds of formula I and their pharmaceutically acceptablesalts can be prepared by methods known in the art, starting either fromcyanuric chloride II (commercial available) or from commerciallyavailable dichloro-intermediates by sequential substitution of thechloro-atoms, as shown in the Schemes 1 and 2.

When R³ or R⁴ is hydrogen, the replacement of the chloro atom can bedone by reduction with Pd on charcoal and hydrogen, as described forexample in J. Am. Chem. Soc. 78, 2477 (1956).

When R³ or R⁴ is lower alkyl, the replacement of the chloro atom can bedone with alkyl-Grignard reagents, as described for example in Helb. 33,1365 (1950).

When R³ or R⁴ is OR′, the nucleophilic substitution of the chloro atomcan be done by reaction with the corresponding alcohols or alcoholates,in analogy to J. Am. Chem. Soc. 79, 944 (1957) or the correspondingphenolates, in analogy to J. Am. Chem. Soc. 73, 2990 (1951).

When R³ or R⁴ is NR″R′″ then the nucleophilic substitution of the chloroatom can be done with the corresponding amine HNR″R′″, as shown forexample in Bull. Soc. Chim. Fr. 1973, 2112. Alternatively, for lessnucleophilic or sterically hindered amines, the substitution can be doneunder Buchwald-Hartwig conditions, using Pd-catalysis.

When R³ is phenyl or substituted phenyl, the chloro atom can be reactedwith arylboronic acids in presence of a base and a palladium catalyst(Suzuki-coupling, as described, for example, in Tetrahedron 57, 2787(2001)) for other triazine-derivatives.

When R³ is lower alkyl substituted by hydroxy, for example the groupC(CH₃)₂OH, the chloro atom can be alkoxycarbonylated, as described, forexample, in Tetrahedron 55, 405 (1995) for analogouspyrimidine-derivatives. The resulting ester is then reacted withmethylmagnesium halide, as described, for example, in Tetrahedron 61,6330 (2005) for analogous pyridine-derivatives. This procedure is shownin Scheme 3.

Aniline III can be prepared as described in Scheme 4.

Nucleophilic substitution at room temperature or elevated temperature(e.g reflux or under pressure using a microwave oven) under neutralconditions or in the presence of a base (like e.g. potassium carbonate),neat or in a polar solvent (like e.g. THF or DMSO etc.) of a substituted4-nitro-phenyl halide VII (hal=F, Cl, Br, I) with a compound R¹H, (like4-methyl-imidazole) yields a nitro derivative VIII. Alternatively, anitro derivative VIII can be prepared from a suitable precursor, such asa carbonyl derivative IX (R=H or C₁₋₄-alkyl), by applying standardreaction sequences for the formation of the substituent R¹. A nitrocompound VIII can be reduced to an aniline III using generally knownprocedures, e.g. hydrogenation in the presence of a catalyst (like e.g.10% palladium on carbon) in a solvent (like e.g. ethanol or ethylacetate) or, by using a metal (like e.g. iron) or a metal salt (likee.g. stannous chloride) in a polar solvent (like e.g. acetic acid ortetrahydrofuran). Alternatively, aniline III can be prepared byintroducing a substituent R¹ into a N-protected aniline derivative X(PG=protecting group) using generally known procedures, e.g.displacement reactions under catalytic conditions (like e.g.palladium(0) or copper(II) catalysis) or, by forming a group R¹ in aN-protected aniline derivative XI, respectively, and subsequentlycleaving off the protecting group.

The compounds were investigated in accordance with the test givenhereinafter.

Cellular Assay

Human neuroglioma H4 cells overexpressing human APP were plated at30,000 cells/well/200 μl in 96-well plates in IMDM media containing 10%FCS, 0.2 mg/l Hygromycin B and incubated for 2 h at 37° C., 5% CO₂ priorto adding test compounds.

Compounds for testing were dissolved in 100% Me₂SO yielding in a 10 mMstock solution. Typically 12 μl of these solutions were further dilutedin 1000 μl of IMDM media (w/o FCS,). Sub sequential 1:1 dilutions gave aten point dose response curve. 100 μl of each dilution was added to thecells in 96-well plates. Appropriate controls using vehicle only andreference compound were applied to this assay. The final concentrationof Me₂SO was 0.4%. After incubation for 22 hrs at 37° C., 5% CO₂, 50 μlsupernatant was transferred into round-bottom 96-well polypropyleneplates for detection of Aβ42. 50 μl assay buffer (50 mM Tris/Ck, pH 7.4,60 mM NaCl, 0.5% BSA, 1% TWEEN 20) was added to the wells followed bythe addition of 100 μl of detection antibody (ruthenylated Aβ42-specificantibody BAP15 0.0625 μg/mL in assay buffer). 50 μl of a premix ofcapture antibody (biotinylated 6E10 antibody, 1 μg/mL) andSteptavidin-coated magnetic beads (Dynal M-280, 0.125 mg/mL) werepreincubated for 1 hr at room temperature before adding the assayplates. Assay plates were incubated on a shaker for 3 hrs at roomtemperature and finally read in the Bioveris M8 Analyser according tothe manufacturer's instructions (Bioveris).

Toxicity of compounds was monitored by a cell viability test of thecompound-treated cells using a colorimetric assay (CellTiter 96™ AQassay, Promega) according to the manufacturer's instructions. Briefly,after removal of 50 μl cell culture supernatant for detection of Aβ42,20 μl of 1×MTS/PES solution was added to the cells and incubated for 30min at 37° C., 5% CO₂. Optical density was then recorded at 490 nm.

IC₅₀ values for inhibition of Aβ42 secretion were calculated bynonlinear regression fit analysis using XLfit 4.0 software (IDBS).

The preferred compounds show a IC₅₀<1.0 (μM). In the list below aredescribed data of γ-secretase inhibition for some compounds of theinvention:

IC₅₀ in vitro Example No. (μM) 2 0.19 3 0.38 4 0.87 5 0.25 6 0.95 7 0.709 0.45 11 0.32 13 0.20 16 0.23 17 0.12 19 0.91 21 0.93 23 0.16 25 0.7226 0.59

The present invention also provides pharmaceutical compositionscontaining compounds of the invention, for example, compounds of formulaI or pharmaceutically acceptable salts thereof and a pharmaceuticallyacceptable carrier. Such pharmaceutical compositions can be in the formof tablets, coated tablets, dragées, hard and soft gelatin capsules,solutions, emulsions or suspensions. The pharmaceutical compositionsalso can be in the form of suppositories or injectable solutions.

The pharmaceutical compositions of the invention, in addition to one ormore compounds of the invention, contain a pharmaceutically acceptablecarrier. Suitable pharmaceutically acceptable carriers includepharmaceutically inert, inorganic or organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acids or its salts and thelike can be used, for example, as such carriers for tablets, coatedtablets, dragées and hard gelatin capsules. Suitable carriers for softgelatin capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like. Depending on the nature ofthe active substance no carriers are, however, usually required in thecase of soft gelatin capsules. Suitable carriers for the production ofsolutions and syrups are, for example, water, polyols, glycerol,vegetable oil and the like. Suitable carriers for suppositories are, forexample, natural or hardened oils, waxes, fats, semi-liquid or liquidpolyols and the like.

The pharmaceutical compositions can, moreover, contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

The present invention also provides a process for the manufacture ofpharmaceutical compositions. Such process comprises bringing thecompound of formula I and/or pharmaceutically acceptable acid additionsalt thereof and, fir desired, one or more other therapeuticallyvaluable substances into a galenical administration form together withone or more therapeutically inert carriers.

In accordance with the invention compounds of formula I as well as theirpharmaceutically acceptable salts are useful in the control orprevention of illnesses based on the inhibition of the γ-secretase, suchas of Alzheimer's disease.

The dosage at which compounds of the invention can be administered canvary within wide limits and will, of course, have to be adjusted to theindividual requirements in each particular case. In the case of oraladministration the dosage for adults can vary from about 0.01 mg toabout 1000 mg per day of a compound of general formula I or of thecorresponding amount of a pharmaceutically acceptable salt thereof. Thedaily dosage can be administered as single dose or in divided doses and,in addition, the upper limit can also be exceeded when this is found tobe indicated.

Tablet Formulation (Wet Granulation)

mg/tablet Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound offormula I 5 25 100 500 2. Lactose Anhydrous DTG 125 105 30 150 3. Sta-Rx1500 6 6 6 30 4. Microcrystalline Cellulose 30 30 30 150 5. MagnesiumStearate 1 1 1 1 Total 167 167 167 831

Manufacturing Procedure

1. Mix items 1, 2, 3 and 4 and granulate with purified water.2. Dry the granules at 50° C.3. Pass the granules through suitable milling equipment.4. Add item 5 and mix for three minutes; compress on a suitable press.

Capsule Formulation

mg/capsule Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound offormula I 5 25 100 500 2. Hydrous Lactose 159 123 148 — 3. Corn Starch25 35 40 70 4. Talc 10 15 10 25 5. Magnesium Stearate 1 2 2 5 Total 200200 300 600

Manufacturing Procedure

1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.2. Add items 4 and 5 and mix for 3 minutes.3. Fill into a suitable capsule.

Example 1(4,6-Dimethoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine

a) 1-(2-Methoxy-4-nitro-phenyl)-4-methyl-1H-imidazole

A solution of 2-chloro-5-nitroanisole (187 mg, 1 mmol), of4-methyl-1H-imidazole (335 mg, 4 mmol) and of potassium hydroxide (99mg, 1.5 mmol) in DMSO (0.86 mL) was stirred for 5 h at 80° C. under anatmosphere of nitrogen. After cooling to 20° C. the reaction was pouredonto ice-water. A precipitation was formed and the suspension wasstirred for 15 min. The solid was filtered off, washed with water,dissolved in dichloromethane, dried over sodium sulfate, filtered andthe solvent was evaporated under reduced pressure to yield a yellowsolid. The crude product was purified on silica gel usingdichloromethane/methanol (19:1 v/v) as eluent to yield the titlecompound (106 mg, 45%) as a pale-yellow solid. Alternatively the productcan be also crystallized from the crude material from diethyl ether.

MS ISP (m/e): 234.3 (100) [(M+H)⁺].

¹H NMR (CDCl₃, 300 MHz): δ (ppm)=7.97 (d, 1H), 7.96 (s, 1H), 7.83 (s,1H), 7.42 (d, 1H), 7.00 (s, 1H), 4.00 (s, 3H), 2.31 (s, 3H).

b) 3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine

1-(2-Methoxy-4-nitro-phenyl)-4-methyl-1H-imidazole (2.52 g, 10.8 mmol)dissolved in ethanol (110 mL) was stirred under an atmosphere ofhydrogen at 20° C. for 3.5 h in the presence of 10% palladium oncharcoal (0.25 g). The catalyst was filtered off and washed withethanol. The solvent of the filtrate was evaporated under reducedpressure. The crude product was purified on silica gel usingdichloromethane/methanol (19:1 v/v) as eluent. The fraction containingthe product was suspended in diethyl ether, stirred for 15 min, filteredand dried to yield the title compound (1.72 g, 78%) as a yellow solid.

MS ISP (m/e): 204.3 (100) [(M+H)⁺].

¹H NMR (CDCl₃, 300 MHz): δ (ppm)=7.48 (s, 1H), 6.91 (d, 1H), 6.88 (s,1H), 6.35 (s, 1H), 6.17 (d, 1H), 3.68 (s, 3H), 2.11 (s, 3H).

c)(4,6-Dimethoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine

Palladium acetate (5.0 mg, 0.022 mmol) and(2-biphenylyl)dicyclohexylphosphine (16 mg, 0.046 mmol) were dissolvedunder an atmosphere of argon in dioxane (2 mL) and stirred for 10 min at20° C. This solution was added at 20° C. under an atmosphere of nitrogento a flask containing 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine(116 mg, 0.57 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (100 mg, 0.57mmol) and potassium carbonate (1.57 g, 11.4 mmol) in 3 ml of dioxane.The resulting mixture was refluxed over night under argon, poured into asaturated aqueous solution of sodium chloride and extracted 3 times withethyl acetate. The organic layer was dried, evaporated and the residuepurified by column chromatography on silica gel usingdichloromethane/methanol (98:2 v/v) as eluent to yield the titlecompound (18 mg, 9%) as a yellowish solid.

MS ISP (m/e): 343.0 (100) [(M+H)⁺].

¹H NMR (DMSO-D₆, 300 MHz): δ (ppm)=10.31 (s broad, 1H), 7.85 (s, 1H),7.30 (s, 2H), 7.06 (s, 1H), 3.94 (s broad, 6H), 3.80 (s, 3H), 2.14 (s,3H).

Example 2N-(4-Chloro-phenyl)-6-methoxy-N′-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[1,3,5]triazine-2,4-diamine

a)(4-Chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine

Triethylamine (0.23 ml, 1.62 mmol) was added to a solution of3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (300 mg, 1.48 mmol) in5 ml of methanol. The mixture was cooled in an ice-bath and2,4-dichloro-6-methoxy-[1,3,5]triazine (266 mg, 1.48 mmol) addedportionwise. The mixture was stirred for 1 hour at 0° C. The resultingprecipitate was removed by filtration and dried to give the titlecompound as a slightly brownish solid (317 mg, 62%).

MS ISP (m/e): 345.3 (100) & 347.2 (40) [(M+H)⁺].

¹H NMR (DMSO-D₆, 300 MHz): δ (ppm)=10.85 (s broad, 1H), 7.78 (s broad,1H), 7.71 (s, 1H), 7.45-7.20 (m, 2H), 7.09 (s, 1H), 4.00 (s broad, 3H),3.82 (s, 3H), 2.16 (s, 3H).

b)N-(4-Chloro-phenyl)-6-methoxy-N′-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[1,3,5]-triazine-2,4-diamine

The title compound was prepared from(4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amineand 4-chloroaniline in analogy to example 1c). It was obtained in 15%yield as a colorless solid.

MS ISP (m/e): 438.2 (100) & 440.3 (37) [(M+H)⁺].

¹H NMR (CDCl3, 300 MHz): δ (ppm)=7.66 (s, 1H), 7.53 (d, 2H), 7.46 (sbroad, 1H), 7.35-7.05 (m, 6H), 6.88 (s, 1H), 4.01 (s, 3H), 3.38 (sbroad, 3H), 2.30 (s, 3H).

Example 3[3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-methoxy-6-(2-trifluoromethyl-phenoxy)-[1,3,5]triazin-2-yl]-amine

A mixture of(4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine(70 mg, 0.2 mmol), 2-hydroxybenzotrifluoride (34 mg, 0.21 mmol) andpotassium carbonate (31 mg, 0.22 mmol) in 5 ml acetonitrile was refluxedovernight. Water was added to the mixture. The product was extractedwith ethylacetate, concentrated and purified by trituration with diethylether to give the title compound as colorless solid (43 mg, 45%).

MS ISP (m/e): 473.2 (100) [(M+H)⁺].

¹H NMR (CDCl3, 300 MHz): δ (ppm)=7.72 (d, 1H), 7.62 (t, 2H), 7.50 (sbroad, 1H), 7.39 (t, 1H), 7.35-7.25 (m, 2H), 7.10 (s broad, 1H), 6.85 (sbroad, 1H), 4.00 (s, 3H), 3.85 & 3.05 (two s, total 3H), 2.29 (s, 3H).

Example 4[4-(4-Fluoro-phenoxy)-6-methoxy-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine

The title compound was prepared from(4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amineand 4-fluorophenol in analogy to example 3. It was purified by columnchromatography on silica gel using ethyl acetate as eluent to give thetitle compound as a yellowish solid in 52% yield.

MS ISP (m/e): 421.4 (100) [(M+H)⁺].

¹H NMR (CDCl3, 300 MHz): δ (ppm)=7.62 (s, 1H), 7.55-6.90 (m, 8H), 4.00(s, 3H), 3.70 (s broad, 3H), 2.30 (s, 3H).

Example 5N-(4-Chloro-phenyl)-6-methoxy-N′-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N-methyl-[1,3,5]triazine-2,4-diamine

This compound was prepared from(4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amineand 4-chloro-N-methylaniline in analogy to example 1c. It was purifiedby column chromatography on Si—NH2 gel (Isolute) using ethyl acetate aseluent to give the title compound as a colorless solid in 14% yield.

MS ISP (m/e): 452.2 (100) & 454.2 (39)[(M+H)⁺].

¹H NMR (CDCl3, 300 MHz): δ (ppm)=7.62 (s, 1H), 7.38 (d, 2H), 7.30-6.80(m, 6H), 6.85 (s, 1H), 3.95 (s broad, 3H), 3.65 (s broad, 3H), 3.51 (s,3H), 2.30 (s, 3H).

Example 6[3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-methoxy-6-(3,4,5-trifluoro-phenoxy)-[1,3,5]triazin-2-yl]-amine

This compound was prepared from(4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amineand 3,4,5-trifluorophenol in analogy to example 3. Chromatography onsilica gel using ethyl acetate as an eluent gave the title compound as acolorless solid in 25% yield.

MS ISP (m/e): 457.5 (100) [(M+H)⁺].

¹H NMR (CDCl3, 300 MHz): δ (ppm)=7.64 (s, 1H), 7.55-6.85 (m, 6H), 4.02(s, 3H), 3.71 (s broad, 3H), 3.51 (s, 3H), 2.30 (s, 3H).

Example 7[3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4-methoxy-6-piperidin-1-yl-[1,3,5]triazin-2-yl)-amine

This compound was prepared from(4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amineand piperidine in analogy to example 1c. Chromatography on Si—NH2 gel(Isolute) using ethyl acetate as an eluent gave the title compound as acolorless solid in 22% yield.

MS ISP (m/e): 396.1 (100) [(M+H)⁺].

¹H NMR (CDCl3, 300 MHz): δ (ppm)=7.72 (s, 1H), 7.63 (s, 1H), 7.17 (d,1H), 6.97 (d, 1H), 6.94 (s, 1H), 6.87 (s, 1H), 3.94 (s, 3H), 3.85 (s,3H), 3.81 (t broad, 4H), 2.30 (s, 3H), 1.75-1.65 (m 2H), 1.65-1.55 (m,4H).

Example 86-Chloro-N-[3-methoxy-4-(4-methyl-imidazol-1-yl-phenyl]-N′,N′-dimethyl-[1,3,5]triazine-2,4-diamine

(4-Chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine(800 mg, 3.94 mmol) was dissolved in 10 ml of methanol and cooled in anice-bath. Triethylamine (0.6 ml, 4.33 mmol) was added, followed by(4,6-dichloro-[1,3,5]triazin-2-yl)-dimethyl-amine (760 mg, 3.94 mmol;Chem. Pharm. Bull. 45, 291 (1997)). The resulting slurry was stirred for1 hour at 0° C. and filtered, to give the title compound as a slightlybrownish solid in 57% yield.

MS ISP (m/e): 360.2 (100) & 362.3 (46) [(M+H)⁺].

¹H NMR (DMSO-D₆, 300 MHz): δ (ppm)=10.22 (s broad, 1H), 7.90 (s broad,1H), 7.68 (s, 1H), 7.35-7.15 (m, 2H), 7.06 (s, 1H), 3.70 (s, 3H), 3.20(s, 3H), 3.13 (s, 3H), 2.13 (s, 3H).

Example 9[4-(2,4-Dichloro-phenoxy)-6-methoxy-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine

This compound was prepared from(4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amineand 2,4-dichlorophenol in analogy to example 3. Chromatography on silicagel using ethyl acetate as an eluent gave the title compound as acolorless solid in 81% yield.

MS ISN (m/e): 471.4 (100) [(M−H)⁻].

¹H NMR (CDCl3, 300 MHz): δ (ppm)=7.62 (s, 1H), 7.48 (d, 1H), 7.40-7.10(m, 4H), 6.88 (s, 1H), 4.01 (s, 3H), 3.75 (s broad, 3H), 2.30 (s, 3H).

Example 10[3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-(2-trifluoromethyl-phenoxy)-[1,3,5]triazin-2-yl]-amine

a)(4-Chloro-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine

This compound was prepared from3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and2,4-dichloro-1,3,5-triazine in analogy to example 2a. The compoundprecipitated from methanol in 50% yield.

MS ISP (m/e): 317.1 (100) & 319.2 (38) [(M+H)⁺].

¹H NMR (DMSO-D₆, 300 MHz): δ (ppm)=10.90 (s, 1H), 8.68 (s broad, 1H),7.73 (s, 1H), 7.60 (s, 1H), 7.36 (s, 1H), 7.09 (s, 1H), 3.81 (s, 3H),2.15 (s, 3H).

b)[3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-(2-trifluoromethyl-phenoxy)-[1,3,5]-triazin-2-yl]-amine

This compound was prepared from(4-chloro-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amineand 2-hydroxybenzotrifluoride in analogy to example 3. Chromatography onsilica gel using ethyl acetate as an eluent gave the title compound as acolorless solid in 33% yield.

MS ISN (m/e): 441.4 (100) [(M−H)⁻].

¹H NMR (CDCl3, 300 MHz): δ (ppm)=8.57 (s broad, 1H), 7.74 (d, 1H),7.70-6.90 (m, 8H), 6.86 (s, 1H), 3.75 and 3.13 (two broad s, total 3H),2.29 (s, 3H)

Example 11N-(4-Chloro-phenyl)-N′-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N-methyl-[1,3,5]triazine-2,4-diamine

This compound was prepared from(4-chloro-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amineand 4-chloro-N-methylaniline in analogy to example 1c. Chromatography onSi—NH2 gel (Isolute) using ethyl acetate as an eluent gave the titlecompound as a colorless solid in 23% yield.

MS ISN (m/e): 420.3 (100) & 422.4 (29) [(M−H)⁻].

¹H NMR (CDCl3, 300 MHz): δ (ppm)=8.32 (s broad, 1H), 7.62 (s, 1H), 7.40(d, 2H), 7.28 (d, 2H), 7.12 (s broad, 2H), 7.00 (s broad, 1H), 6.86 (s,1H), 3.72 (s broad, 3H), 3.53 (s, 3H)

Example 12[3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-methoxy-6-(pyridin-3-yloxy)-[1,3,5]triazin-2-yl]-amine

The title compound was prepared from(4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amineand 3-hydroxypyridine in analogy to example 3. It was purified by columnchromatography on Si—NH2 gel (Isolute) using ethyl acetate as eluent togive the title compound as a yellowish solid in 21% yield.

MS ISN (m/e): 404.6 (100) [(M−H)⁻].

¹H NMR (CDCl3, 300 MHz): δ (ppm)=8.57 (d, 1H), 8.53 (dxd, 1H), 7.65-7.50(m, 2H), 7.40-7.30 (m, 2H), 7.25-6.90 (m, 2H), 6.86 (s, 2H), 4.01 (s,3H), 3.73 & 3.62 (two broad s, total 3H), 2.29 (s, 3H).

Example 13[4-(2-Chloro-pyridin-3-yloxy)-6-methoxy-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine

The title compound was prepared from(4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amineand 2-chloro-3-hydroxypyridine in analogy to example 3. It was purifiedby column chromatography on Si—NH2 gel (Isolute) using ethyl acetate aseluent to give the title compound as a yellowish solid in 76% yield.

MS ISN (m/e): 484.6 (100) [(M−H)⁻].

¹H NMR (CDCl3, 300 MHz): δ (ppm)=7.75-7.50 (m, 3H), 7.40-6.80 (m, 5H),3.87 & 3.73 (two s, total 3H), 3.27 & 3.22 (two s, total 3H), 2.30 (s,3H).

Example 14[3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-[4-methoxy-6-(2-methyl-pyridin-3-yloxy)-[1,3,5]triazin-2-yl]-amine

The title compound was prepared from(4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amineand 3-hydroxy-2-methylpyridine in analogy to example 3. It was purifiedby column chromatography on Si—NH2 gel (Isolute) using ethyl acetate aseluent to give the title compound as a yellowish solid in 34% yield.

MS ISP (m/e): 420.2 (100) [(M+H)⁺].

¹H NMR (CDCl3, 300 MHz): δ (ppm)=8.44 (d, 1H), 7.62 (s, 1H), 7.44 (d,1H), 7.35-7.05 (m, 4H), 6.85 (s, 1H), 4.01 (s, 3H), 3.83 & 3.58 (twobroad s, total 3H), 2.48 (s, 3H), 2.29 (s, 3H).

Example 15[4-((2S,6R)-2,6-Dimethyl-morpholin-4-yl)-6-methoxy-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine

The title compound was prepared from(4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amineand cis-2,6-dimethylmorpholine in analogy to example 1c. It was purifiedby column chromatography on Si—NH2 gel (Isolute) using ethyl acetate aseluent to give the title compound as a yellowish solid in 58% yield.

MS ISP (m/e): 426.3 (100) [(M+H)⁺]

¹H NMR (CDCl3, 300 MHz): δ (ppm)=7.68 (s, 1H), 7.63 (s, 1H), 7.17 (d,1H), 7.00-6.90 (m, 2H), 6.87 (s, 1H), 4.60 (d broad, 2H), 3.96 (s, 3H),3.86 (s, 3H), 3.70-3.50 (m, 2H), 2.62 (t broad, 2H), 2.30 (s, 3H), 1.24(d, 6H).

Example 16[4-Isopropoxy-6-(2-trifluoromethyl-phenoxy)-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine

a)(4-Chloro-6-isopropoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine

The title compound was prepared from3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and2,4-dichloro-6-isopropoxy-[1,3,5]triazine (Synth. Commun. 24, 2153(1994)) in analogy to example 2a. The compound crystallized frommethanol as a slightly brownish solid in 41% yield.

MS ISN (m/e): 373.3 (100) & 375.4 (33) [(M−H)⁻].

¹H NMR (DMSO-D₆, 300 MHz): δ (ppm)=10.78 (s broad, 1H), 7.71 (s, 1H),7.63 (s broad, 1H), 7.40-7.20 (m, 2H), 7.08 (s, 1H), 5.28 (sept, 1H),3.80 (s, 3H), 2.15 (s, 3H), 1.35 (d, 6H).

b)[4-Isopropoxy-6-(2-trifluoromethyl-phenoxy)-[1,3,5]-triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine

This compound was prepared from(4-chloro-6-isopropoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amineand 2-hydroxy benzotrifluoride in analogy to example 3. Chromatographyon silica gel using ethyl acetate as an eluent gave the title compoundas a colorless solid in 99% yield.

MS ISP (m/e): 501.3 (100) [(M+H)⁺]

¹H NMR (CDCl3, 300 MHz): δ (ppm)=7.60 (s, 1H), 7.55-7.30 (m, 4H),7.15-6.85 (m, 3H), 6.85 (s, 1H), 5.20 (m, 1H), 3.52 (s, 3H), 2.29 (s,3H), 1.36 (d; 6H).

Example 17N-(4-Chloro-phenyl)-6-isopropoxy-N′-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N-methyl-[1,3,5]triazine-2,4-diamine

This compound was prepared from(4-chloro-6-isopropoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amineand 4-chloro-N-methyl aniline in analogy to example 1c. Chromatographyon Si—NH2 gel (Isolute) using ethyl acetate as an eluent gave the titlecompound as a colorless solid in 27% yield.

MS ISP (m/e): 480.3 (100) [(M+H)⁺]

¹H NMR (CDCl3, 300 MHz): δ (ppm)=7.60 (s, 1H), 7.40-7.35 (m, 4H), 7.27(d, 2H), 7.15-6.90 (m, 3H), 6.85 (s, 1H), 5.21 (s broad, 1H), 4.40-3-30(s very broad, 3H), 3.51 (s, 3H), 2.30 (s, 3H), 1.36 (s broad, 6H).

Example 18[3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4-methoxy-6-methyl-[1,3,5]triazin-2-yl)-amine

a) 2-Chloro-4-methoxy-6-methyl-[1,3,5]triazine

A solution of 2,4-dichloro-6-methoxy-1,3,5-Triazine (1.0 g, 5.56 mmol)in 10 ml of dioxane was treated with a 1.2 molar solution ofdimethylzinc in toluene (4.63 ml, 5.56 mmol). The mixture was stirredovernight at room temperature, poured into 100 ml of water and extractedwith ethyl acetate. Chromatography on silica gel using heptane/ethylacetate 9:1 v/v gave the title compound (225 mg, 25%) as a colorlesssolid.

MS (m/e): 159.0 (32) [(M⁺)]

¹H NMR (DMSO-D₆, 300 MHz): δ (ppm)=4.00 (s, 3H), 2.51 (s, 3H).

b)[3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4-methoxy-6-methyl-[1,3,5]triazin-2-yl)-amine

This compound was prepared from3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and2-chloro-4-methoxy-6-methyl-[1,3,5]triazine in analogy to example 1c. Itwas purified by chromatography on Si—NH2 (Isolute) using ethyl acetateas an eluent to give the title compound as a slightly yellowish solid in32% yield.

MS ISP (m/e): 480.3 (100) [(M+H)⁺]

¹H NMR (CDCl3, 300 MHz): δ (ppm)=7.69 (s, 1H), 7.65 (s, 1H), 7.21 (d,1H), 7.08 (dxd, 1H), 6.88 (s, 1H), 4.03 (s, 3H), 3.87 (s, 3H), 2.48 (s,3H), 2.29 (s, 3H).

Example 19(4,6-Diisopropoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine

To 2-propanol (321 mg, 5.34 mmol) was added metallic sodium (9 mg, 0.39mmol). The resulting alcoholate-solution was treated with(4-chloro-6-isopropoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine(100 mg, 0.27 mmol) and the resulting mixture refluxed for 3 hours.Water was added and the product extracted with ethyl acetate. The crudematerial was purified by chromatography on Si—NH2 gel (Isolute) usingethyl acetate as an eluent to give the title compound as a colorlesssolid (71 mg, 67%).

MS ISP (m/e): 399.2 (100) [(M+H)⁺]

¹H NMR (CDCl3, 300 MHz): δ (ppm)=7.63 (d, 1H), 7.49 (d, 1H), 7.22 (d,1H), 7.25-7.15 (m, 2H), 7.08 (dxd, 1H), 6.87 (s, 1H), 5.32 (sept., 2H),3.86 (s, 3H), 2.30 (s, 3H); 1.40 (d, 12H).

Example 206-Methoxy-N-(2-methoxy-ethyl)-N′-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N-methyl-[1,3,5]triazine-2,4-diamine

This compound was prepared from(4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amineand N-(2-methoxyethyl)methylamine in analogy to example 1c. It waspurified by chromatography on Si—NH2 (Isolute) using ethyl acetate as aneluent to give the title compound as a slightly yellowish solid in 51%yield.

MS ISP (m/e): 400.2 (100) [(M+H)⁺]

¹H NMR (CDCl3, 300 MHz): δ (ppm)=7.78 & 7.65 (two s, total 1H), 7.63 (d,1H), 7.16 (d, 1H), 7.05-6.95 (m, 2H), 6.87 (s, 1H), 3.96 & 3.94 (two s,total 3H), 3.85 (s, 3H), 3.90-3.75 (m, 2H), 3.15-3.05 (m, 2H), 3.36 &3.35 (two s, total 3H), 3.26 & 3.23 (two s, total 3H), 2.29 (s, 3H).

Example 21(1-{4-Methoxy-6-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-[1,3,5]triazin-2-yl}-piperidin-4-yl)-aceticacid ethyl ester

A suspension of(4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine(100 mg, 0.29 mmol) and ethyl-2-(piperidin-4-yl)acetate hydrochloride(63 mg, 0.30 mmol) in 3 ml of methanol was treated with triethylamine(0.13 ml, 0.92 mmol). The mixture was stirred for 3 hours at roomtemperature, concentrated and the product purified by chromatography onsilica gel using ethyl acetate as an eluent. The title compound wasisolated as a colorless solid (137 mg, 99%).

MS ISP (m/e): 482.3 (100) [(M+H)⁺]

¹H NMR (CDCl3, 300 MHz): δ (ppm)=7.68 (d, 1H), 7.62 (s, 1H), 7.16 (d,1H), 7.00-6.90 (m, 2H), 6.87 (s, 1H), 4.79 (d broad, 2H), 4.15 (qa, 2H),3.94 (s, 3H), 3.84 (s, 3H), 2.92 (t broad, 2H), 2.35-2.20 (m, 5H),2.20-2.00 (m, 1H), 1.81 (d broad, 2H), 1.35-1.15 (m, 5H).

Example 22N-[3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N′,N′-dimethyl-6-(4-methyl-piperazin-1-yl)-[1,3,5]triazine-2,4-diamine

6-Chloro-N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N′,N′-dimethyl-[1,3,5]triazine-2,4-diamine(100 mg, 0.28 mmol) was treated with N-methylpiperidine (0.31 ml, 2.78mmol). The mixture was heated to 50° C. for 30 minutes, diluted withwater and extracted with ethyl acetate. Purification by chromatographyon silica gel using ethyl acetate as an eluent to gave the titlecompound (114 mg, 97%) as a yellowish gum.

MS ISP (m/e): 424.3 (100) [(M+H)⁺]

¹H NMR (CDCl3, 300 MHz): δ (ppm)=7.79 (d, 1H), 7.61 (d, 1H), 7.13 (d,1H), 6.93 (dxd, 1H), 6.86 (s, 1H), 6.79 (s, 1H), 3.90-3.80 (m, 7H), 3.15(s, 6H), 2.43 (t broad, 4H), 2.35 (s, 3H), 2.29 (s, 3H).

Example 23[4,6-Bis-(2-trifluoromethyl-phenoxy)-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine

a)(4,6-Dichloro-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine

A solution of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (1.0 g,4.92 mmol) and triethylamine (0.75 ml, 5.42 mmol) in 15 ml of methanolwas cooled in an ice-bath and cyanuric chloride (889 mg, 4.82 mmol)added portionwise. The mixture was stirred for 1 hour at 0° C.Filtration of the precipitate gave the title compound (1.115 g, 65%) asa slightly brownish solid.

MS ISP (m/e): 351.2 (100) & 353.1 (56) [(M+H)⁺]

¹H NMR (DMSO-D₆, 300 MHz): δ (ppm)=11.29 (s, 1H), 7.81 (s, 1H), 7.54 (d,1H), 7.41 (d, 1H), 7.29 (dxd, 1H), 7.13 (s, 1H), 3.81 (s, 3H), 2.16 (s,3H).

b)[4,6-Bis-(2-trifluoromethyl-phenoxy)-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine

A mixture of 2-hydroxybenzotrifluoride (95 mg, 0.59 mmol) and potassiumcarbonate (87 mg, 0.63 mmol) in 10 ml of acetonitrile was treated with(4,6-dichloro-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine.The suspension was refluxed overnight, diluted with water and extractedwith ethyl acetate. Chromatography on silica gel using ethyl acetate asthe eluent gave the title compound (17 mg, 10%) as a slightly brownishsolid.

MS ISP (m/e): 603.2 (100) [(M+H)⁺]

¹H NMR (CDCl3, 300 MHz): δ (ppm)=7.69 (d, 2H), 7.65-7.50 (m, 3H),7.45-7.20 (m, 5H), 7.04 (d, 1H), 6.84 (d, 2H), 3.56 & 3.49 (two s, total3H), 2.28 (s, 3H).

Example 243-({4-Methoxy-6-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-[1,3,5]triazin-2-yl}-methyl-amino)-propane-1,2-diol

A mixture of(4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine(100 mg, 0.29 mmol) and 3-methyl-1,2-propanediol (606 mg, 5.76 mmol) washeated for 2 hours at 60° C. The reaction mixture was diluted with waterand extracted with ethyl acetate. The organic phase was dried,concentrated and the title compound (85 mg, 71%) isolated as a slightlybrownish solid by trituration in diethyl ether.

MS ISP (m/e): 416.3 (100) [(M+H)⁺]

¹H NMR (CDCl3, 300 MHz): δ (ppm)=7.75-7.60 (m, 1H), 7.20-7.00 (m, 3H),6.87 (s broad, 1H), 4.05-3.90 (m, 3H), 3.84 (s, 3H), 3.90-3.40 (m, 7H),3.26 & 3.24 (two s, total 3H), 2.29 (s, 3H).

Example 25[4-(4-Chloro-benzyloxy)-6-methoxy-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine

To a solution of 4-chlorobenzyl alcohol (45 mg, 0.32 mmol) in 10 ml oftetrahydrofuran was added metallic sodium (7 mg, 0.30 mmol). The mixturewas stirred until the sodium dissolved.(4-Chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine(100 mg, 0.29 mmol) was added and the mixture refluxed for 4 hours,diluted with water and extracted with ethyl acetate. The product waspurified by chromatography on Si—NH2 (Isolute) using ethyl acetate as asolvent to give the title compound (26 mg, 20%) as a colorless solid.

MS ISP (m/e): 453.2 (100) [(M+H)⁺]

¹H NMR (CDCl3, 300 MHz): δ (ppm)=7.64 (s, 1H), 7.50 (s broad, 1H),7.45-7.25 (m, 5H), 7.20 (d, 1H), 7.10 (d, 1H), 6.88 (s, 1H), 5.41 (s,2H), 4.03 (s, 3H), 3.85 (s, 3H), 2.30 (s, 3H).

Example 26(1-{4-Methoxy-6-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-[1,3,5]triazin-2-yl}-piperidin-4-yl)-aceticacid

4-Piperidineacetic acid hydrochloride (381 mg, 2.12 mmol) was suspendedin 10 ml of methanol. Triethylamine (0.9 ml, 6.45 mmol) was added,followed by(4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine(700 mg, 2.02 mmol). The resulting mixture was stirred overnight at roomtemperature, concentrated and subjected to column chromatography onSi—NH2 (Isolute) using dichloromethane/methanol 95:5 v/v as an eluent.The material isolated was further purified by several triturations inwater to give the final compound (792 mg, 87%) as a slightly brownishsolid.

MS ISN (m/e): 452.2 (100) [(M−H)⁻].

¹H NMR (DMSO-D₆, 300 MHz): δ (ppm)=12.20 (s broad, 1H), 9.72 (s, 1H),7.89 (s, 1H), 7.67 (d, 1H), 7.30-7.15 (m, 2H), 7.04 (s, 1H), 4.65 (sbroad, 2H), 3.86 (s, 3H), 3.79 (s, 3H), 3.10-2.80 (m, 2H), 2.19 (d, 2H),2.14 (s, 3H), 2.05-1.90 (m, 1H), 1.74 (d broad, 2H), 1.25-1.05 (m, 2H).

Example 27(1-{4-[4-(2-Chloro-pyridin-3-yloxy)-6-methoxy-[1,3,5]triazin-2-ylamino]-2-methoxy-phenyl}-1H-imidazol-4-yl)-methanol

a) [1-(2-Methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]-methanol

A mixture of 1-fluoro-2-methoxy-4-nitro-benzene (1.0 g, 5.8 mmol),(1H-imidazol-4-yl)-methanol (602 mg, 6.1 mmol) and cesium carbonate(2.86 g, 8.8 mmol) in 40 ml of acetonitrile was refluxed overnight. Thereaction mixture was concentrated in vacuo, diluted with water andextracted with ethyl acetate. Chromatography on Si—NH2 (Isolute) usingethyl acetate as an eluent gave the title compound as a yellowish solid.

MS ISP (m/e): 250.1 (51) [(M+H)⁺]

¹H NMR (CDCl3, 300 MHz): δ (ppm)=8.00-7.85 (m, 3H), 7.45 (d, 1H), 7.26(d, 1H), 4.70 (s, 2H), 4.01 (s, 3H).

b) [1-(4-Amino-2-methoxy-phenyl)-1H-imidazol-4-yl]methanol

[1-(2-Methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]methanol (500 mg, 2.0mmol) and stannous chloride dehydrate (2.35 g, 10.4 mmol) were suspendedin a mixture of 40 ml of ethyl acetate and 20 ml of methanol. Thereaction mixture was refluxed for 1 hour, cooled to room temperature anddiluted with aqueous sodium hydrogencarbonate solution. Extraction withethyl acetate gives the title compound (311 mg, 71%) as a yellowishviscous oil.

MS ISP (m/e): 220.1 (46) [(M+H)⁺]

¹H NMR (CDCl3, 300 MHz): δ (ppm)=7.61 (s, 1H), 7.01 (d, 2H), 6.35-6.25(m, 2H), 4.66 (s, 2H), 3.85 (s broad, 2H), 3.77 (s, 3H).

c){1-[4-(4-Chloro-6-methoxy-[1,3,5]triazin-2-ylamino)-2-methoxy-phenyl]-1H-imidazol-4-yl}-methanol

This compound was prepared in analogy to example 8 from[1-(4-amino-2-methoxy-phenyl)-1H-imidazol-4-yl]-methanol, triethylamineand 2,4-dichloro-6-methoxy-1,3,5-triazine. The title compound wasisolated as a brownish solid in 61% yield.

MS ISN (m/e): 361.3 (100) & 363.4 (34) [(M−H)⁻].

¹H NMR (DMSO-D₆, 300 MHz): δ (ppm)=10.86 (s broad, 1H), 7.79 (d, 1H),7.45-7.25 (m, 2H), 7.22 (s, 1H), 4.93 (t broad, 1H), 4.39 (d broad, 2H),4.00 (s, 3H), 3.82 (s, 3H).

d)(1-{4-[4-(2-Chloro-pyridin-3-yloxy)-6-methoxy-[1,3,5]triazin-2-ylamino]-2-methoxy-phenyl}-1H-imidazol-4-yl)-methanol

This compound was prepared in analogy to example 3 from{1-[4-(4-chloro-6-methoxy-[1,3,5]triazin-2-ylamino)-2-methoxy-phenyl]-1H-imidazol-4-yl}-methanoland 2-chloro-3-hydroxypyridine. The title compound was isolated as aslightly brownish solid in 43% yield.

MS ISP (m/e): 220.1 (46) [(M+H)⁺]

¹H NMR (DMSO-D₆, 300 MHz): δ (ppm)=10.50 (s broad, 1H), 8.39 (dxd, 1H),8.00 (d, 1H), 7.90-7.65 (m, 2H), 7.65-7.50 (m, 1H), 7.40-7.10 (m, 2H),4.39 (s, 2H), 3.96 (s, 3H), 3.80 (s broad, 3H).

Example 28[4-(2-Chloro-pyridin-3-yloxy)-6-methoxy-[1,3,5]triazin-2-yl]-(4-imidazol-1-yl-phenyl)-amine

a)(4-Chloro-6-methoxy-[1,3,5]triazin-2-yl)-(4-imidazol-1-yl-phenyl)-amine

This compound was prepared in analogy to example 8 from4-(imidazol-1-yl)aniline, triethylamine and2,4-dichloro-6-methoxy-1,3,5-triazine. The title compound was isolatedas a slightly brownish solid in 84% yield.

MS ISP (m/e): 303.3 (100) & 305.2 (47) [(M+H)⁺]

¹H NMR (DMSO-D₆, 300 MHz): δ (ppm)=10.82 & 10.70 (two broad s, total1H), 8.22 (s, 1H), 7.90-7.60 (m, 5H), 7.11 (s, 1H), 3.97 (s, 3H).

b)[4-(2-Chloro-pyridin-3-yloxy)-6-methoxy-[1,3,5]-triazin-2-yl]-(4-imidazol-1-yl-phenyl)-amine

This compound was prepared in analogy to example 3 from(4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-(4-imidazol-1-yl-phenyl)-amineand 2-chloro-3-hydroxypyridine. The title compound was isolated as acolorless solid in 37% yield.

MS ISP (m/e): 396.1 (100) & 398.2 (44) [(M+H)⁺]

¹H NMR (CDCl3, 300 MHz): δ (ppm)=8.37 (d, 1H), 7.81 (s, 1H), 7.60 (dxd,1H), 7.45-7.30 (m, 4H), 7.30-7.20 (m, 3H), 4.00 (s, 3H).

Example 29(S)-2-({4-Methoxy-6-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-[1,3,5]triazin-2-yl}-methyl-amino)-2-phenyl-ethanol

a) (R)-2-Methylamino-2-phenyl-ethanol

Lithium aluminum hydride (1.84 g, 43 mmol) was suspended in 30 ml oftetrahydrofuran and cooled in an ice-bath. A solution of(R)-methylamino-phenyl acetic acid (1.0 g, 6 mmol) in 10 ml oftetrahydrofuran was slowly added over a period of 20 minutes. Theresulting mixture was stirred for 1 hour at 0°, 4 hours at roomtemperature and then refluxed overnight. The mixture was cooled andcarefully hydrolysed by addition of 50 ml 15% aqueous sodium hydroxide.Extraction with ethyl acetate gives a crude oil which was purified bychromatography on silica gel using heptane/ethyl acetate 9:1 v/v to givethe title compound as a slightly yellowish oil (0.36 g, yield=39%).

MS ISP (m/e): 152.2 (100) [(M+H)⁺]

¹H NMR (CDCl₃, 300 MHz): δ (ppm)=7.40-7.25 (m, 5H), 3.75-3.35 (m, 3H),2.36 (s, 3H), 1.80 (s broad, 2H).

b)(S)-2-({4-Methoxy-6-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-[1,3,5]triazin-2-yl}-methyl-amino)-2-phenyl-ethanol

This compound was prepared from(4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amineand (R)-2-methylamino-2-phenyl-ethanol in analogy to example 1c.Purification by chromatography on Si—NH2 gel (Isolute) using ethylacetate as an eluent gave the title compound as a colorless solid in 32%yield.

MS ISP (m/e): 462.2 (100) [(M+H)⁺]

¹H NMR (CDCl₃, 300 MHz): δ (ppm)=7.80-6.80 (m, 10H), 6.23 (d broad, 1H),4.35-4.05 (m, 2H), 3.97 (d, 3H), 3.85-3.65 (m, 3H), 2.99 (d, 3H), 2.28(s, 3H), 1.61 (s broad, >1H).

Example 302-{4-Methoxy-6-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-[1,3,5]triazin-2-yl}-propan-2-ol

a)4-Methoxy-6-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-[1,3,5]triazine-2-carboxylicacid methyl ester

A solution of(4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine(0.35 g, 1.0 mmol) in a mixture of 7 ml methanol and 3.5 ml ethylacetate was treated with triethylamine (0.21 ml, 1.5 mmol) andtris(dibenzylideneacetone) dipalladium dichloromethane-complex (70 mg,0.09 mmol). The mixture was transferred to an autoclave, flushed withcarbon monoxide and hold 20 hours at 80° C. under a pressure of 5 bar ofcarbon monoxide. After cooling and evacuating the carbon monoxide, themixture was concentrated to about 2 ml and diluted again with a mixtureof ethyl acetate/methanol 9:1 v/v.

The title compound precipitated as an intensely yellow solid aftercooling in the refrigerator for 17 hours. Yield=55%.

MS ISP (m/e): 371.3 (100) [(M+H)⁺]

¹H NMR (CDCl₃, 300 MHz): δ (ppm)=7.80-7.50 (m, 2H), 7.22 (s, 1H), 7.08(s broad, 1H), 6.89 (s, 1H), 4.12 (s, 3H), 4.03 (s, 3H), 3.88 (s, 3H),2.30 (s, 3H).

b)2-{4-Methoxy-6-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-[1,3,5]triazin-2-yl}-propan-2-ol

A slurry of4-methoxy-6-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-[1,3,5]triazine-2-carboxylicacid methyl ester (105 mg, 0.28 mmol) in 2 ml of tetrahydrofuran wastreated at room temperature with a 3M solution of methyl magnesiumchloride (0.5 ml, 1.5 mmol) in tetrahydrofuran. After stirring for 90minutes at room temperature, the heterogenous mixture was hydrolyzed byaddition of 20 ml of water. The mixture was extracted with ethyl acetateand the final product purified by chromatography on Si—NH2 gel (Isolute)using cyclohexane/ethyl acetate (gradient 60 to 100% ethyl acetate). Thetitle compound was isolated as a colorless solid in a yield of 43%.

MS ISP (m/e): 371.2 (100) [(M+H)⁺]

¹H NMR (CDCl₃, 300 MHz): δ (ppm)=7.67 (s, 1H), 7.40 (s broad, 1H), 7.22(s, 1H), 7.10 (s broad, 1H), 6.90 (s, 1H), 4.22 (s broad, 1H), 4.07 (s,3H), 3.88 (s, 3H), 2.31 (s, 3H), 1.56 (s, 6H).

Example 31N-[3-Methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N′,N′-dimethyl-6-(2-trifluoromethyl-phenoxy)-[1,3,5]triazine-2,4-diamine

6-Chloro-N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-N′,N′-dimethyl-[1,3,5]triazine-2,4-diamine(200 mg, 0.56 mmol) in 7 ml acetonitrile was treated with2-hydroxy-benzotrifluoride (95 mg, 0.59 mmol) and potassium carbonate(85 mg, 0.62 mmol). The resulting mixture was stirred under reflux for 5days. The mixture was then diluted with 25 ml of water and extractedwith ethyl acetate. Chromatography on silica gel using ethyl acetate asa solvent and subsequent crystallization from methanol gave the titlecompound as colorless solid (42 mg, 16%).

MS ISP (m/e): 486.3 (100) [(M+H)⁺]

¹H NMR (CDCl₃, 300 MHz): δ (ppm)=7.69 (d, 1H), 7.65-7.55 (m, 3H),7.40-7.30 (m, 2H), 7.10 (d, 1H), 7.00 (s, 1H), 6.93 (d broad, 1H), 6.85(s, 1H), 3.73 (s broad, 2H), 3.21 (s, 3H), 3.09 (s, 3H), 2.29 (s, 3H).

Example 32[4-(4-Fluoro-phenyl)-6-methoxy-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine

A mixture of(4-chloro-6-methoxy-[1,3,5]triazin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine(150 mg, 0.43 mmol), 4-fluorobenzeneboronic acid (67 mg, 0.48 mmol),tetrakis-(triphenylphosphin)-palladium (20 mg, 0.02 mmol) and sodiumcarbonate (92 mg, 0.87 mmol) in 3 ml of dioxane was refluxed overnight.The mixture was diluted with water, extracted with ethyl acetate andpurified by chromatography on silica gel using ethyl acetate as aneluent to give the title compound as a colorless solid (84 mg,yield=47%).

MS ISP (m/e): 486.3 (100) [(M+H)⁺]

¹H NMR (CDCl₃, 300 MHz): δ (ppm)=8.49 (t broad, 2H), 7.69 (d, 2H), 7.40(s broad, 1H), 7.25-7.10 (m, 4H), 6.91 (s, 1H), 4.12 (s, 3H), 3.91 (s,3H), 2.32 (s, 3H).

Example 33[4-Chloro-6-(4-chloro-benzyl)-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine

a) 2,4-Dichloro-6-(4-chloro-benzyl)-[,3,5]triazine

An aliquot (12 mL) of a solution of 4-chlorobenzyl chloride (3.94 g,24.0 mmol) in diethyl ether (60 mL) was added to a mixture of magnesiumturnings (0.58 g, 24 mmol) and diethyl ether (20 mL). The mixture washeated to reflux, and subsequently, the residual solution was added dropwise over 1 h at 20 to 30° C. Stirring was continued at 20° C. for 2hours, and thereafter, the freshly prepared Grignard solution was addeddrop wise over 15 min at 10 to 15° C. to a solution of cyanuric chloride(3.76 g, 20 mmol) in toluene (40 mL) cooled in an ice-bath.

The reaction mixture was stirred at 0° C. for 1 h and thereafter allowedto warm to 20° C. over 2 h. Stirring was continued for 15 h at 20° C.The reaction mixture was poured onto saturated aqueous ammonium chloridesolution and the mixture was extracted with ethyl acetate. The organiclayer was washed with water, dried over sodium sulfate, and the solventwas removed under reduced pressure. The residue was stirred with heptane(20 mL) for 30 minutes at 20° C. The solid formed was isolated byfiltration to give the title compound (2.4 g, 44%) as a light yellowsolid. ¹H-NMR (CDCl₃, 300 MHz): δ (ppm)=7.31 (s, 4H), 4.14 (s, 2H).

b)[4-Chloro-6-(4-chloro-benzyl)-[1,3,5]triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine

2,4-Dichloro-6-(4-chloro-benzyl)-[1,3,5]triazine (0.78 g, 2.8 mmol) wasadded at 5° C. to a solution of3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (0.61 g, 3.0 mmol) andtriethylamine (0.36 ml, 0.26 mmol) in 15 ml of methanol. The mixture wasstirred at 5° C. for 1 h and thereafter evaporated under reducedpressure. The residual material was purified by chromatography on silicagel using heptane/0-100% ethyl acetate as eluent to give the titlecompound (0.53 g, 40%) as a yellow viscous oil.

MS ISP (m/e): 441.2 [(M+H)⁺].

¹H NMR (CDCl₃, 300 MHz): δ (ppm)=7.67 (s, 1H), 7.60 (s, 1H), 7.30 (m,4H), 7.20 (d, 1H), 7.02 (dd, 1H), 6.89 (s, 1H), 4.03 (s broad, 2H), 3.85(s broad, 3H), 3.72 (s broad, 3H), 2.30 (s, 3H).

Example 344-(4-Chloro-benzyl)-6-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-[1,3,5]-triazine-2-carboxylicacid methyl ester

This compound was prepared from[4-chloro-6-(4-chloro-benzyl)-[1,3,5]-triazin-2-yl]-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine(0.60 g, 1.36 mmol) in analogy to example 30 a. The crude product waspurified by chromatography on silica gel using heptane/0-80% ethylacetate as eluent to give the title compound (0.41 g, 64%) as a yellowsolid.

MS ISP (m/e): 465.3 [(M+H)⁺].

¹H NMR (CDCl₃, 300 MHz): δ (ppm)=7.66 (s, 1H), 7.58 (s, 1H), 7.30 (m,4H), 7.20 (d, 1H), 6.98 and 7.05 (2 dd, 1H), 6.88 (s, 1H), 4.19 and 4.02(2 s broad, 2H), 4.01 and 3.97 (2 s broad, 3H), 3.80 and 3.70 (2 sbroad, 3H), 2.30 (s, 3H).

1. A compound of formula I

wherein R¹ is hydrogen, lower alkyl or is lower alkyl substituted byhydroxy; R² is hydrogen, lower alkoxy or lower alkyl; R³ and R⁴ are eachindependently hydrogen, halogen, lower alkyl, C(O)O-lower alkyl, OR′,NR″R′″, lower alkyl substituted by halogen or hydroxy, or is phenyl orbenzyl, each of which is optionally substituted by one or two halogenatoms; R′ is lower alkyl, or is phenyl, benzyl or pyridinyl, whereinephenyl, benzyl or pyridinyl are each optionally substituted by one ormore halogen, lower alkyl or lower alkyl substituted by fluoro; R″ ishydrogen or lower alkyl; R′″ is lower alkyl, lower alkyl substituted byone or two hydroxy groups, CH(CH₂OH)-phenyl, —(CH₂)₂O-lower alkyl, orphenyl substituted by halogen, or R″ and R′″ together with the N-atom towhich they are attached form a heterocyclic ring, optionally substitutedby one or more lower alkyl, CH₂C(O)O-lower alkyl, or CH₂C(O)OH; Ar is afive-membered heteroaryl group; or a pharmaceutically active acidaddition salt thereof.
 2. The compound of claim 1, wherein Ar isimidazol-1-yl.
 3. The compound of claim 2, wherein one of R³ or R⁴ isNR″R′″ and R″ and R′″ together with the N-atom to which they areattached form a heterocyclic ring, optionally substituted by one or morelower alkyl, CH₂C(O)O-lower alkyl or CH₂C(O)OH.
 4. The compound of claim2, wherein one of R³ or R⁴ is OR′.
 5. The compound of claim 2, whereinone of R³ or R⁴ is NR″R′″ and R″ is H or lower alkyl and R′″ is loweralkyl, lower alkyl substituted by one or two hydroxy groups,—(CH₂)₂OCH₃, or phenyl substituted by halogen.
 6. The compound of claim1, wherein one of R³ and R⁴ is halogen.
 7. The compound of claim 1,wherein one of R³ and R⁴ is lower alkyl.
 8. The compound of claim 1,wherein one of R³ and R⁴ is C(O)O-lower alkyl.
 9. The compound of claim1, wherein one of R³ and R⁴ is OR′.
 10. The compound of claim 1, whereinone of R³ and R⁴ is NR″R′″.
 11. The compound of claim 1, wherein one ofR³ and R⁴ is lower alkyl substituted by halogen or hydroxyl.
 12. Thecompound of claim 1, wherein one of R³ and R⁴ is phenyl optionallysubstituted by one or two halogen atoms.
 13. The compound of claim 1,wherein one of R³ and R⁴ is benzyl optionally substituted by one or twohalogen atoms.
 14. A pharmaceutical composition comprising atherapeutically effective amount of a compound of formula I

wherein R¹ is hydrogen, lower alkyl or is lower alkyl substituted byhydroxy; R² is hydrogen, lower alkoxy or lower alkyl; R³ and R⁴ are eachindependently hydrogen, halogen, lower alkyl, C(O)O-lower alkyl, OR′,NR″R′″, lower alkyl substituted by halogen or hydroxy, or is phenyl orbenzyl, each of which is optionally substituted by one or two halogenatoms; R′ is lower alkyl, or is phenyl, benzyl or pyridinyl, whereinephenyl, benzyl or pyridinyl are each optionally substituted by one ormore halogen, lower alkyl or lower alkyl substituted by fluoro; R″ ishydrogen or lower alkyl; R′″ is lower alkyl, lower alkyl substituted byone or two hydroxy groups, CH(CH₂OH)-phenyl, —(CH₂)₂O-lower alkyl, orphenyl substituted by halogen, or R″ and R′″ together with the N-atom towhich they are attached form a heterocyclic ring, optionally substitutedby one or more lower alkyl, CH₂C(O)O-lower alkyl, or CH₂C(O)OH; Ar is afive-membered heteroaryl group; or a pharmaceutically active acidaddition salt thereof and a pharmaceutically acceptable carrier.